The objective of this research program is to establish the role of interactions between virus defective interfering particles (DIP), infectious standard virus (S-virus) and lymphocytes in the mechanism of virus persistence and dysfunction of the immune system in chronic viral diseases. Preliminary results showed that lymphoid tissue of mice acutely or persistenly infected with LCMV accumulate high amounts of S-virus and DIP. During the persistent infection, 0.5-3 percent of the lymphocytes (apparently T cells) are infected with attenuated mutants of LCMV. Regulatory interactions appear to exist between S-virus, its attenuated mutants and DIP. The specific topics of this investigation are: a) persistence of virus in lymphocytes, properties of infected cells as well as of the virus which persists, b) latency of S-virus and DIP in lymphocytes, c) production of DIP in lymphocytes and ability of the latter to support DIP-mediated interference with multiplication of homologous S-virus, e) the effect of infection with S-virus, DIP, or DIP plus S-virus on lymphocytes reactivity. Lymphoid cell populations from fetal, newborn or adult mice will be infected in vitro with DIP and S-virus of lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV) or in vivo during LCMV persistence in carrier mice. Productively infected cells will be detected with an infectious center assay. For detection of DIP or of DIP producing lymphocytes after infection with LCMV, a newly developed technique, namely interfering foci forming assay will be employed. The response to stimulation by mitogens and the cytotoxic effect of lymphocytes in a cytotoxic 51Cr release test will be used to estimate the reactivity of lymphocytes. Virus clones isolated from single carrier lymphocytes will be studied. The infected lymphocytes will be characterized by using methods such as cell separation, surface markers, immunofluorescence and electron microscopy. The results of this research may add new knowledge regarding the relationship between viruses and lymphocytes, the mechanism of persistent infection, the regulatory function of DIP and their capacity for in vivo prophylaxis, and may also provide a better methodology for the study of virus-lymphocyte interactions in human diseases.